Control of cell numbers in mammals is believed to be determined, in part, by a balance between cell proliferation and cell death. One form of cell death, sometimes referred to as necrotic cell death, is typically characterized by a pathologic form of cell death resulting from some trauma or cellular injury. Necrotic cell death is harmful to tissues, inducing inflammation and etc. In contrast, another “physiologic” form of cell death usually proceeds in an orderly or controlled manner. This orderly or controlled form of cell death is often referred to as “apoptosis” (Barr, et al., Bio/Technology, 12:487–497, 1994; Steller, et al., 267:1445–1449, 1995). Apoptosis is a programmed cell death by which orgamisms eliminate unwanted cells such as cells whose activity or existence is no longer required without damages to other tissues, thus eliminating damaged or excessive cells. Thus, apoptosis is a fundamentally important physiological process that is required to maintain normal development and homeostasis of an organism.
There are many factors which induce apoptosis. Amonog them, the most important protein is caspase of which 14 kinds are known. Capases are cystein protease enzymes and many important proteins in cells are used as substates for them. The process of apoptosis includes the steps that cells fragmented by caspase family enzymes are uptaken by other cells in small particle form, or eliminated by cells such as marcrophages without accompanying phenomena such as inflammation.
Caspases are classfied into two groups of initiator caspase and effector caspase. The initiator caspase receives the signal of apoptosis and transfers the signal to the effector caspase, and is represented by caspase-8, 9 and etc.
The effector caspase is directly involved in the apoptotic pathway to eliminate various cellular components and is represented by caspase-3, 6, 7 and etc. Among the effector caspases, caspase-3 has been well studied and functions as a final receptor in the apoptotic signal trasduction cascade. It has been shown in many studies that apoptosis can be prevented by inhibiting the expression or activity of caspase-3
Caspase-3 is a 32 kDa cystein protease and an effector caspase which plays an important role during morphogenetic cell death in a mammalian brain. The typical disease induced by the trouble in the apoptotic pathway in which caspases are involved is cancer. Cancer is one of diseases characterized by the failure to undergo apoptosis.
In contrast, the development of continuous apoptosis causes various neurological disorders. Representative diseases mediated by caspase-3 include Alzheimer's disease (Gervais F. G. et al., Cell, 97(3):395–406, 1999; Walter J. et al., Proc Natl Acad Sci USA 96(4):1391–6, 1999; Barnes N. Y. et al., J Neurosci 18(15):5869–80, 1998; Kim T. W. et al., Science 277(5324):373–6, 1997), Huntington's disease (Goldberg Y. P. et al., Nat Genet. 13(4):442–9, 1996; Wellington C. L. et al., J Biol Chem. 273(15):9158–67, 1998; Sanchez I. et al., Neuron. 22(3):623–33, 1999), Parkinson's disease (Dodel R. C. et al., Mol Brain Res 64(1):141–8, 1999; Takai N. et al., J Neurosci Res 54(2):214–22, 1998), ALS (amyltrophic lateral sclerosis) (Pasinelli P. et al., Proc Natl Acad Sci USA. 95(26):15763–8, 1998), AIDS (Kruman I. I. et al., Exp Neurol. 154(2):276–88, 1998), stroke/ischemia (Hara H. et al., Proc Natl Acad Sci USA. 94(5):2007–12, 1997; Namura S. et al., J Neurosci. 18(10):3659–68, 1998; Schulz J. B. et al., Ann Neurol. 45(4):421–9, 1999), traumatic brain injury (Yakovlev A. G. et al., J Neurosci. 17(19):7415–24, 1997; Kermer P. et al., J Neurosci. 18(12):4656–62, 1998; Chaudhary P. et al, Mol Brain Res. 67(1):36–45, 1999), spinal cord injury (Crowe M. J. et al., Nat Med. 3(1):73–6, 1997; Shuman S. L. et al., J Neurosci Res. 50(5):798–808, 1997), osteoarthritis and etc.
Thus, there are many efforts to develop drugs effective against caspase-mediated diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease, ALS, AIDS, stroke/ischemia, traumatic brain injury, spinal cord injury, osteoarthritis and etc. as described in the above by using caspase-3 inhibitors.
Up to now, aspartic acids, peptide compounds, gamma-keto acids have been reported as caspase-3 inhibitors (WO93/05071, WO96.03982, U.S. Pat. No. 5,585,357, WO00/32620, WO00/55157, U.S. Pat. No. 6,153,591)
However, quinoline compounds have not been previously identified as caspase-3 inhibitors.
Under these circumstances, the inventors of this application completed the present invention by developing quinoline derivatives and their pharmaceutically acceptable salts, which have superior inhibitory activity against caspase-3